The present invention pertains to methods for preparing macrocyclic products having 9 or more ring atoms by a ring-closing metathesis of diyne substrates.
By alkyne metathesis there is understood the mutual transalkylidynation of alkynes according to scheme 1.
Usually, reactions of this type are catalyzed by metal compounds (reviews: Schrock, R. R. Polyhedron 1995, 14, 3177; Ivin, K. J.; Mol, J. C. Olefin Metathesis and Metathesis Polymerization, Academic Press, New York, 1997, p 192-223). Contrary to the metathesis of alkenes, which is a well-established field of research today and has found numerous applications in the preparation of technically important products (reviews: Ivin, K. J.; Mol, J. C. Olefin Metathesis and Metathesis Polymerization, Academic Press, New York, 1997; Schuster, M. et al., Angew. Chem. 1997, 109, 2125), in organic chemistry the application of the alkyne metathesis is restricted to the preparation of special polymers (Weiss, K. et al., Angew. Chem. 1997, 109, 522), the ring-opening polymerization of cycloalkynes (Krouse, S. A. et al., Macromolecules 1989, 22, 2569; Zhang, X-P. et al., Macromolecules 1994, 27, 4627) and the dimerization or the cross metathesis of acyclic alkynes (Kaneta, N. et al., Chem. Lett. 1995, 1055; Sancho, J. et al., J. Mol. Cat. 1982, 15, 75; Villemin, D. et al., Tetrahedron Lett 1982, 5139). The metatheses of diynes result in polymeric products by acyclic diyne metathesis (Krouse, S. A. et al., Macromolecules 1989, 22, 2569) or by cyclopolymerization (Fox, H. H. et al. J. Am. Chem. Soc. 1994, 116, 2827; Koo, K.-M. et al., Macromolecules 1993, 26, 2485).
Both heterogeneous and homogeneous transition metal compounds can be used as catalysts or pre-catalysts for alkyne metatheses. Transition metal alkylidyne complexes and transition metal carbyne complexes which may either be added to the reaction mixtures in isolated form or formed in situ from suitable pre-catalysts are regarded as catalytically active species (Katz, T. J. et al., J. Am. Chem. Soc. 1975, 97, 1592). The catalytic activity of transition metal compounds in alkyne metatheses can be increased by the addition of suitable additives such as, e.g., phenol derivatives (Mortreux, A. et al., J. Chem. Soc. Chem. Commun. 1974, 786; Mortreux, A. et al., J. Mol. Cat. 1977, 2, 73; Villemin, D. et al., Tetrahedron Lett. 1982, 5139), aluminium alkyls (Petit, M. et al., J. Chem. Soc. Chem. Commun. 1982, 1385), or SiO2 (Mortreux, A. et al., Bull. Soc. Chim. Fr. 1972, 1641; Mortreux, M. et al. J. Mol. Cat. 1980, 8, 97).
Preferred catalysts or pre-catalysts for alkyne metatheses are Mo(CO)6 (Mortreux, A. et al., J. Chem. Soc. Chem. Commun. 1974, 786; Mortreux, A. et al., J. Mol. Cat. 1977, 2, 73; Villemin, D. et al, Tetrahedron Lett 1982, 5139; Tsonis, C. React. Kinet. Catal. Lett. 1992, 46, 359), MoO2(acac)2/Et3Al (Petit, M. et al., J. Chem. Soc, Chem. Commun. 1982, 1385), MoO3/SiO2 (Mortreux, A. et al., Bull. Soc. Chim. Fr. 1972, 1641; Mortreux, M. et al. J. Mol. Cat. 1980, 8, 97), WoO3/SiO2 (Pennella, F. et al., Chem, Commun 1968, 1548), W(xe2x89xa1CCMe3)(OR)3 or Mo(xe2x89xa1CCMe3)(OR)3 [Rxe2x95x90CMe3, CH(CF3)2, CMe2CF3, CMe(CF3)2, C(CF3)3, C6H3Me2, C6H3i-Pr2, C6H3t-Bu2] (Review: Schrock, R. R., Polyhedron 1995, 14, 3177; Sancho, J. et al., J. Mol. Cat. 1982, 15, 75; Weiss, K. in Carbyne Complexes [Fischer, H. et al., Eds.], Verlag Chemie, Weinheim, 1988, p 220), Re(xe2x89xa1CCMe3)(xe2x95x90NAr)[OCMe(CF3)2]2 (Schrock, R. R. et al., J. Am. Chem. Soc. 1988, 110, 2686; Weinstock, I. A. et al., J. Am. Chem, Soc. 1991, 113, 135), (Me3CO)3Wxe2x89xa1W(OCMe3) or (Me3CO)3Moxe2x89xa1Mo(OCMe3) (Schrock, R. R. Polyhedron 1995, 14, 3177; Krouse, S. A. et al., Macromolecules 1989, 22, 2569; Zhang, X-P. et al., Macromolecules 1994, 27, 4627) and complexes containing a Rexe2x89xa1Re triple bond (Diefenbach, S. P. U.S. Pat. No. 4,698,451, 06. Okt. 1987; Chem. Abstr. 1988, 108, 40092 m).
In the literature both diynes and cycloalkynes have only been used as starting materials for polymerization reactions via alkyne metathesis. Surprisingly, however, we have found that diynes having suitable chain lengths used as substrates can be closed in the presence of suitable catalysts with a high selectivity to yield cycloalkynes, provided the formed cycloalkynes have 12 or more ring atoms (scheme 2).
Furthermore, it turned out that diynes having suitable chain lengths and used as substrates can also be closed with high selectivity to yield cycloalkynes having from 9-11 ring atoms, provided the diyne substrates are conformationally pre-organized for the ring closure by one or several structural elements. Said structural elements comprise rigid backbones, annellated rings, pre-existing double bonds, hydrogen bonds, geminal dialkyl groups, a coordination at metal centers, chiral centers, supramolecular structures.
This access to said class of substances, which is improved and shortened as compared with the previously used methods for preparing cycloalkynes, is important since various cycloalkynes as such are interesting as antibiotics (confer Nicolauo K. C. Angew. Chem. 1991, 103, 1453) and can be converted into other macrocyclic products of economic importance such as, e.g., pharmaceuticals, pheromones, agrochemicals, crown ethers, odorous substances, perfume ingredients, or flavoring agents by existing methods. 
The selectivity of this reaction depends in particular on the structure of the substrates, the used catalyst, the reaction conditions, and the ring strain within the prepared cycloalkyne. The formation of the cycloalkynes is favored by performing the reaction under high dilution in an organic solvent which does not deactivate the catalyst. When determining the concentration of the substrate in the reaction medium, the effective molarity parameter thereof has to be considered (Mandolini, L. Adv. Phys. Org. Chem. 1986, 22, 1). According to the present invention, cycloalkadiyne products can also be obtained at higher concentrations by a cyclodimerization of the diyne substrates according to scheme 3.
In the present invention all metal compounds being active in alkyne metatheses may be catalysts or pre-catalysts regardless of whether they are initially introduced homogeneously or heterogeneously into the reaction medium. The catalysts can be employed in an isolated form or formed in situ within the reaction medium from suitable precursors. The used amount of catalyst is not critical, with preferred amounts of catalyst being within the range from 0.01-10%, based on the used substrate.
Transition metal alkylidyne complexes, transition metal compounds forming alkylidyne complexes under reaction conditions, and transition metal compounds with metal-metal triple bonds are preferred catalysts or pre-catalysts.
The abbreviations used in the following text indicate: i-Pr=isopropyl; t-Bu=tertiary butyl; Ph=phenyl; acac=acetylacetonate; Ar=aryl; gem=geminal; Me=methyl.
Complexes of the general type M(xe2x89xa1CR1)(OR2)3 with
M=Mo, W
R1=C1-C20 alkyl, aryl, alkenyl, alkylthio, dialkylamino, preferably CMe3, Ph
R2=C1-C20 alkyl, aryl, preferably CMe3, CH(CF3)2, CMe2CF3, CMe(CF3)2, C(CF3)3, C6H3Me2, C6H3i-Pr2, C6H3t-Bu2 are especially preferred catalysts or pre-catalysts.
Especially preferred catalysts or pre-catalysts are also complexes of the general type Re(xe2x89xa1CR1)(xe2x95x90NAr)(OR2)2 with
R1=C1-C20 alkyl, aryl, alkenyl, preferably CMe3, Ph
Ar=C6-C20 aryl
R2=C1-C20 alkyl, aryl, preferably CMe3, CH(CF3)2, CMe2CF3, CMe(CF3)2, C(CF3)3, C6H3Me2, C6H3i-Pr2, C6H3t-Bu2 
Especially preferred catalysts or pre-catalysts are also complexes of the general type (RO)3Mxe2x89xa1M(OR)3 with
M=Mo, W
R=C1-C20 alkyl, aryl, preferably CMe3, CH(CF3)2, CMe2CF3, CMe(CF3)2, C(CF3)3.
Preferred catalysts formed in situ within the reaction medium result from mixtures of Mo(CO)6 and phenols. Especially preferred catalysts are formed by using electron-deficient phenols such as trifluoromethylphenolf bis(trifluoromethyl)phenol, fluorophenol, difluorophenol, pentafluorophenol, chlorophenol, dichlorophenol ntachlorophenol. The ratio Mo(CO)6: phenol is not critical; preferred ratios Mo(CO)6: phenol are within the range from 1:1 to 1:1000.
Furthermore, preferred catalysts produced in situ within the reaction medium are formed from mixtures of M[N(R1)Ar]3 and halogen compounds of the R22EX2 or R33SiX types, wherein
M=Mo, W p1 R1=C1-C20 alkyl, secondary alkyl (sec-alkyl), tertiary alkyl (t-alkyl), cycloalkyl, preferably t-Bu
Ar=C6-C20 aryl, preferably C6H5, C6H4Me, C6H3Me2, C6H3(i-Pr)2, C6H3(t-Bu)2, C6H2Me3 
R2=H, F, Cl, Br, I, C1-20 alkyl, aryl
E=C, Si
R3=C1-C20 alkyl, aryl, preferably methyl
X=F, Cl, Br, I
With respect to compounds of the M[N(R1)Ar]3 type see: C. E. Laplaza et al., J. Am. Chem. Soc. 1996, 118, 8623.
The diynes used in the present invention as substrates may contain one or several functional groups in the form of substituents on the chain or heteroatoms within the chain. Said substituents comprise inter alia branched or unbranched alkyl rests, aromatic or non-aromatic carbocyclic rings, aromatic or non-aromatic nitrogen, oxygen, sulfur, or phosphorous containing heterocyclic rings, carboxylic acids, esters, ethers, epoxides, silyl ethers, thioethers, thioacetals, disulfides, alcohols, anhydrides, imines, silyl ethers, silylenol ethers, ammonium salts, amines, amides, nitriles, perfluoroalkyl groups, gem-dialkyl groups, alkenes, halogens, ketones, ketals, aldehydes, acetals, carbamates, carbonates, urethanes, ureas, sulfonates, sulfones, sulfonamides, sulfoxides, phosphates, phosphonates, nitro groups, organosilane moieties, or metal centers. The presence of said functional groups within the substrates can favor the formation of the macrocyclic cycloalkyne products. Representative examples are summarized in table 1 and in the examples.
The diynes used as substrates may be conformationally pre-organized for the ring closure by structural elements such as, e.g., chiral centers, hydrogen bonds, supramolecular structures, rigid backbones, coordination at metal centers. Substrates which do not have any one of these structural elements and which are conformationally flexible for this reason may be used as well. The substrates may be present in a supported form.
Diynes with R1, R2xe2x89xa0H are preferred substrates. Especially preferred substrates are diynes in which the moieties R1 and R2 in schemes 2 and 3 are selected such that a low-molecular alkyne R1Cxe2x89xa1CR2 (e.g., 2-butyne, 2-hexyne, 3-hexyne) is formed as a by-product of the formation of the macrocyclic cycloalkyne.
The reactions are performed such that the respective substrates are contacted with the homogeneous or heterogeneous catalyst. Normally, this is effected by mixing a solution or suspension of the substrate with a solution or suspension of the catalyst. Depending on the used catalyst and substrate the reaction temperature can be varied, from xe2x88x9230xc2x0 C. to +200xc2x0 C. being preferably used. The reaction time is not critical and can be varied between several minutes and several days. The reactions are preferably performed under an inert atmosphere (e.g., argon, nitrogen, helium).
In general, hydrocarbons (e.g., hexane, octane, petroleum ether, toluene, xylenes, cumene, decalin) or halogenated hydrocarbons (e.g., chlorobenzene, bromobenzene, fluorobenzene, trifluoromethylbenzene, dichlorobenzene, trichlorobenzene, tetrachloromethan, 1,2-dichloroethane) are preferred as solvents for the ring-closing diyne metatheses yielding macrocyclic cycloalkynes. When selecting suitable catalysts, other solvents such as, e.g., acetonitrile, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, dimethyl formamide, dimethyl sulfoxide, phenol may be used. Mixtures of said solvents may be used as well.
The reactions can be performed at pressures below atmospheric pressure. Applying a reduced pressure can result in the elimination of volatile by-products R1Cxe2x89xa1CR2 and thus increase the obtained cycloalkyne yield. The reduced pressure applicable in each case depends on the specific properties of the substrate, the formed cycloalkyne, the alkyne R1Cxe2x89xa1CR2 obtained as by-product according to schemes 2 and 3, the used solvent, and any additives. In addition, the low-molecular by-product R1Cxe2x89xa1CR2 can be stripped off the reaction mixture by passing an inert gas flow through the reaction mixture, which results in an increase of the cycloalkyne yield.
The recovery of the reaction mixtures and the purification of the products is not critical and depends on the respective physical properties of the produced products and/or the unreacted substrates. Preferred recovery and purification methods are distillation, sublimation, crystallization, chromatography, filtration, and extraction.
The macrocyclic cycloalkynes accessible according to the present invention may be used for the synthesis of numerous resultant products, e.g., by a reduction, oxidation, or cycloaddition of the triple bond and additions to the triple bond. The possibility to convert the macrocyclic cycloalkynes accessible by the present invention into macrocyclic cycloalkenes having uniform configurations of the double bond by suitable reactions (e.g., partial hydrogenation, hydrometalation, carbometalation) is particularly important.
Normally, macrocyclic cycloalkenes having a uniform configuration of the double bond are not accessible by a ring-closing metathesis (RCM) of dienes. In most cases the RCM yields mixtures of the respective (E)- and (Z)-isomers with the (E) isomer being often formed preferably (Schuster M. et al., Angew. Chem. 1997, 109, 2125; Fxc3xcrstner, A. Topics in Catalysis 1997, 4, 285; Fxc3xcrstner, A. et al. Synthesis 1997, 792). The present invention, however, enables the selective preparation of macrocyclic, (Z)-configured cycloalkenes by reacting the cycloalkynes obtained from the ring-closing metathesis of diynes using suitable reactions such as, e.g., a partial hydrogenation or hydrometalation/protonation (reviews: March, J. Advanced Organic Chemistry, 4th Ed., Wiley, New York, 1992, p 771ff; Marvell, E. N. et al. Synthesis 1973, 457; Fxc3xcrstner, A. et al. J. Org. Chem. 1997, 62, 2332). Here, the cycloalkynes accessible by the present invention can initially be isolated and thereafter converted into the (Z)-configured cycloalkene according to a suitable method. Alternatively, the formation of the macrocyclic cycloalkyne by a ring-closing alkyne metathesis of a diyne substrate and the conversion thereof into a macrocyclic, (Z)-configured cycloalkene in one single reaction batch is performed successively within the meaning of an integrated chemical method.
Macrocyclic cycloalkenes having a (Z)-configured double bond are often used as antibiotics, pharmaceuticals for human or veterinary medicine, pheromones, odorous substances, perfume ingredients etc. A representative example for the synthesis of a pharmaceutically relevant macrocyclic product by oxidation of a macrocyclic cycloalkene are epothilone and analogues of this compound. If the (Z)-configured cycloalkene required for the synthesis of epothilone or the analogues thereof is prepared by RCM, usually (E)/(Z)-mixtures are obtained, however, only the respective (Z)-alkenes thereof can be converted into epothilone or the analogues of this natural substance having the correct configuration of the stereogeneous centers of the formed epoxides by epoxidizing the double bond (Nicolaou, K. C. et al. Angew. Chem. 1996, 108, 2554; Meng, D. J. Am. Chem. Soc. 1997, 119, 2733; Taylor, R. E. Tetrahedron Lett. 1997, 2061; Schinzer, D. et al. Angew. Chem. 1997, 109, 543; Yang, Z. Angew. Chem. 1997, 109, 170; Bertinato, P. J. Org. Chem. 1996, 61, 8000; Nicolaou, K. C. et al. J. Am. Chem. Soc. 1997, 119, 7960; Nicolaou K. C. et al. Nature 1997, 387, 268; Nicolaou, K. C. et al. Chem. Eur. J. 1997, 3, 1957; Nicolaou K. C. et al., Angew. Chem. 1997, 109, 2181). Said synthesis and similar syntheses may be designed stereoselectively and consequently considerabely improved by forming the macrocyclic cycloalkyne and subsequently partially reducing said cycloalkyne to the (Z)-cycloalkene.
The examples specified hereinafter describe prototypical ring-closing reactions of diynes to macrocyclic products by alkyne metathesis catalysts under preferred conditions, however, said examples should by no means limit the scope, the scope of application, or the advantages of the present invention.